2'-acetonaphthone

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

A 90-day repeated dose toxicity study was performed to investigate the toxic nature of 1-(2-naphthyl)ethanone in 15 male and 15 female rats of the FDRL strain. The test chemical was diluted in cotton seed oil in a concentration sufficient to provide the predetermined dosage in 2% of the diet. The daily consumption of the test chemical was 33 mg/kg body weight/day for males and 36.9 mg/kg body weight/day for females. The individual body weight and food consumption was recorded during the administrating period. In addition, haematological and blood chemical determinations were made on 8 rats of each sex at a 6-week period, and in all rats at 12 weeks. The tests were terminated at 90 days and at autopsy, liver and kidney weights were recorded. The following organs from half the animals in each group were taken for histological examination: liver, kidneys, stomach, small and large intestines, spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spinal cord, bladder, adrenals, thyroid, pituitary, gonads, salivary glands, and lymph nodes. Measurements of growth, haematological and blood clinical chemical analysis, gross and histological examination of the major organs revealed no significant adverse effects, related to the test chemical administration. Hence, the repeated exposure to 1-(2-naphthyl)ethenone up to concentration of 33 and 36.9 mg/kg body weight/day exerted no specific target organ toxicity when administered in feed to rats for 90 days.The NOAEL (No Observed Adverse Effect Level ) of the test chemical was considered to be 33 mg/kg body weigh/day for males and 36.9 mg/kg body weight/day for females.

Repeated dose toxicity: Inhalation

2'-acetonaphthone (CAS no 93-08-3) has very low vapor pressure of 0.0009 mm Hg at 21.9°C. So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely. Also, the particle size distribution was determined in the range of 500 micrometer to 1000 micron.Therefore this end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for2'-acetonaphthone (CAS no 93-08-3)(as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

A 90-day repeated dose toxicity study was performed to investigate the toxic nature of 1-(2-naphthyl)ethanone following dietary administration to male and female rats.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: FDRL

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: Housed individually in wiremesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow ad libitum
- Water (e.g. ad libitum): Fresh water ad libitum
- Acclimation period: No data

Route of administration:

oral: feed

Vehicle:

cotton seed oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical was diluted with cotton seed oil in a concentration sufficient to provide the predetermined dosage in 2% of the diet. The daily consumption of the test chemical was 33 mg/kg body weight/day for males and 36.9 mg/kg body weight/day for females.

DIET PREPARATION
- Rate of preparation of diet (frequency): biweekly
- Mixing appropriate amounts with (Type of food): commercial diet (Purina Laboratory Chow)
- Storage temperature of food: No data
VEHICLE
- Justification for use and choice of vehicle (if other than water): Cotton seed oil
- Concentration in vehicle: 0, 33 mg/kg/day (males) and 36.9 mg/kg/day (females)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

control

Dose / conc.:

33 mg/kg bw/day (nominal)

Remarks:

male

Dose / conc.:

36.9 mg/kg bw/day (nominal)

Remarks:

female

No. of animals per sex per dose:

15 male and 15 female rats

Control animals:

yes, plain diet

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: No data
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Efficiency of food utilization (EFU), body weight gain (g)/ 100 g food eaten.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on 8 rats of each sex at a 6-week period, and in all rats at 12 weeks
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: No data
- How many animals: 15 males and 15 females
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on 8 rats of each sex at a 6-week period, and in all rats at 12 weeks
- Animals fasted: No data
- How many animals: 15 males and 15 females
- Parameters checked in table [No.?] were examined. No data
URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER:

Sacrifice and pathology:

The test was terminated at 90 days and at autopsy, liver and kidney weights were recorded and the following organs from half the animals in each group were taken for histological examination: liver, kidneys, stomach, small and large intestines, spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spinal cord, bladder, adrenals, thyroid, pituitary, gonads, salivary glands, and lymph nodes.

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

-Measurements of growth, haematological and blood clinical chemical analysis, gross and histological examination at necropsy revealed no adverse effects related to the test chemical administration.

-No significant test chemical-related gross pathological and histopathological changes were observed at autopsy in any rats.

Key result

Dose descriptor:

NOAEL

Effect level:

33 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical biochemistry

food consumption and compound intake

food efficiency

gross pathology

haematology

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Key result

Dose descriptor:

NOAEL

Effect level:

36.9 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

clinical biochemistry

food consumption and compound intake

food efficiency

gross pathology

haematology

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Critical effects observed:

no

Conclusions:

The NOAEL of 1-(2-naphthyl)ethanone for repeated dose exposure was considered to be 33 mg/kg body weigh/day for males and 36.9 mg/kg body weigh/day for females.

Executive summary:

A 90-day repeated dose toxicity study was performed to investigate the toxic nature of 1-(2-naphthyl)ethanone in 15 male and 15 female rats of the FDRL strain.The test chemical was diluted in cotton seed oil in a concentration sufficient to provide the predetermined dosage in 2% of the diet. The daily consumption of the test chemical was 33 mg/kg body weight/day for males and 36.9 mg/kg body weight/day for females. The individual body weight and food consumption was recorded during the administrating period. In addition, haematological and blood chemical determinations were made on 8 rats of each sex at a 6-week period, and in all rats at 12 weeks. The tests were terminated at 90 days and at autopsy, liver and kidney weights were recorded. The following organs from half the animals in each group were taken for histological examination: liver, kidneys, stomach, small and large intestines, spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spinal cord, bladder, adrenals, thyroid, pituitary, gonads, salivary glands, and lymph nodes.Measurements of growth, haematological andbloodclinical chemicalanalysis,gross and histological examinationof the major organsrevealed no significant adverse effectsrelated to the test chemical administration.Hence,the repeated exposure to 1-(2-naphthyl)ethenone up to concentration of 33 and 36.9 mg/kg body weight/day exerted no specific target organ toxicity when administered in feed to rats for 90 days.The NOAEL (NoObservedAdverseEffectLevel ) of the test chemical was considered to be 33 mg/kgbody weigh/dayper day for males and 36.9 mg/kgbody weight/dayfor females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

33 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K2 level data

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data available for the test chemicals was reviewed to determine the toxic nature upon repeated exposure. The studies are as mentioned below:

Repeated dose toxicity: Oral

Study 1

A 90-day repeated dose toxicity study was performed to investigate the toxic nature of 1-(2-naphthyl)ethanone in 15 male and 15 female rats of the FDRL strain. The test chemical was diluted in cotton seed oil in a concentration sufficient to provide the predetermined dosage in 2% of the diet. The daily consumption of the test chemical was 33 mg/kg body weight/day for males and 36.9 mg/kg body weight/day for females. The individual body weight and food consumption was recorded during the administrating period. In addition, haematological and blood chemical determinations were made on 8 rats of each sex at a 6-week period, and in all rats at 12 weeks. The tests were terminated at 90 days and at autopsy, liver and kidney weights were recorded. The following organs from half the animals in each group were taken for histological examination: liver, kidneys, stomach, small and large intestines, spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spinal cord, bladder, adrenals, thyroid, pituitary, gonads, salivary glands, and lymph nodes. Measurements of growth, haematological and blood clinical chemical analysis, gross and histological examination of the major organs revealed no significant adverse effects, related to the test chemical administration. Hence, the repeated exposure to 1-(2-naphthyl)ethenone up to concentration of 33 and 36.9 mg/kg body weight/day exerted no specific target organ toxicity when administered in feed to rats for 90 days.The NOAEL (No Observed Adverse Effect Level ) of the test chemical was considered to be 33 mg/kg body weigh/day for males and 36.9 mg/kg body weight/day for females.

Study 2

A 28-day repeated dose toxicity study was performed to determine the toxicity likely to arise after repeated oral exposure to 2-methoxynaphthalenein male and female Sprague-Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight(bw)/day for 28 consecutive days. The control group was administered with groundnut oil as vehicle in this study. Clinical signs, body weight and food consumption were recorded during the administration period. Assessment of locomotor activity and ophthalmological examinations were performed on all rats at the 4th week of test chemical administration. After the completion of dosing period, blood samples were collected for haematology and for clinical biochemistry analysis. All animals were sacrificed on termination day and examined for gross lesion. Organ weights were recorded then were preserved for further histopathological examinations including reproductive organs (testis, ovaries, uterus). Two males of 500 mg/kg bw/day group died on the 7th week of the treatment, but the rest of animals survived throughout the treatment period of 28 days. Clinical signs like nasal discharge, red crust around the nostrils were present in all groups including control. In addition, there were few cases of snuffling, eye lid swelling, hunched back posture in the treated groups the occurrence of these clinical signs increased with doses in both sexes. Significant reduction in the mean body weighs in comparison to the control were seen in the 500 mg/kg bw/day group, on day 8, 15, 28 in males and on day 8, 15, and 22 on females. On the termination day, in both sexes the mean body weights remained lower than those of controls. No changes in food and water consumption were seen at any dose level. No effects on food and water consumption were observed at any dose level. as compared to control. No abnormalities were found in the ophthalmological examination in both the high-dose and control groups. The locomotor activity of all treated rats was similar to the control. Haematological and clinical biochemistry analysis revealed significant changes in several parameters both in male and female animals but none of them showed clear dose-dependence and were present in both sexes. Significant decrease in MCHC (mean corpuscular haemoglobin concentration) were detected in the middle- and high doses in males although in females the MCHC level was comparable to control at all dose groups. The blood testosterone concentration significantly increased at 500 mg/kg while in females the blood estrogen level increased significantly in the middle- but not in the high-dose group. At middle- and high dose group the levels of potassium and albumin were found significantly increased in females, but no changes of these parameters were observed among males. At necropsy, nasal discharge, red crust around nostril, wet perineum, bloated stomach, viscous oily secretion inside the thoracic cavity, small white solid mass slightly firm in consistency floating inside the urinary bladder were among the gross post-mortem findings observed in all group including the control. Although the incidences of these findings were elevated in the high-dose group they could be also produced by adaptive metabolic and physiological changes during anaesthesia and terminal sacrifice therefore they were considered unattributable to the test chemical administration. Gross lesions of the lung, lever, spleen, and intestine were found in four male and four females at 500 mg/kg bw/day, while abnormalities were found only in three control animals. In females the relative weights of ovaries were significantly less in low- middle- and high-dose groups and the uterus weighted significantly less at highest dose in comparison to control. In addition, the spleen weighted significantly less in comparison with controls in the middle- and high-dose group. In males the relative weights of testis and heart weighted significantly more than those of the control and the relative liver weight increased significantly in the low-dose. However, no microscopic abnormalities supporting the changes in organ weights were found during detailed histological evaluations of the respective organs neither in male nor in female animals. Therefore, the observed changes in organ weights were considered incidental with no toxicological relevance. No further remarkable, test chemical-related histopathological alterations of vital organs were observed in the 500 mg/kg/day group in comparison with the vehicle control group. The few microscopic findings which were seen in the high-dose group including collapsed lung with focal inflammation, focal fatty change and excess of lymphocytes in liver, inflammation in intestine, reactive spleen were also observed in the control groups. In summary, the repeated exposure to 500 mg/kg bw/day of2-methoxynaphthalenewas slightly toxic in both male and female SD rats as evidenced by the significantly reduced bodyweight. However, no conclusive and dose-dependent changes were found in blood tests (haematology and clinical biochemistry). The gross pathological findings were not supported by histopathological alterations at any dose groups and were not accompanied with organ disfunction. Hence, the NOAEL and LOAEL values were set as 250 mg/kg bw/day and 500 mg/kg bw/day, respectively.

Study 3

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed to determine the repeated-dose toxicity of Acetophenone (Cas No. 98-86-2) in Sprague-Dawley rats. The test chemical was administered in concentrations of 0, 75, 225 and 750 mg/kg/day once daily by oral gavage for a minimum of four weeks up to and included the scheduled day of euthanasia (day 33/34). Cage-side observations for overt signs of toxicity were performed once daily while detailed clinical observations were performed weekly. An abbreviated functional observation battery (FOB) including home cage removal from home cage and open field evaluation, was performed for all males and females beginning on day -1 and weekly thereafter. Following 28 days of treatment, an abbreviated functional observation battery was performed for 10 males in the control and the high-dose groups. Manipulative tests were performed for 10 males in the control and low-dose (75 mg/kg/day) groups, 5 males in the middle and high-dose groups (225 and 750 mg/kg/day). Motor activity was conducted in 5 males from the control and high dose groups. A full functional observation battery was performed on 5 females from each group. Individual body weights and food consumption were recorded on days 0,3,7, 12, 16,20,23,27 and 30. Blood samples were collected from five males and five females from each group on the day of scheduled euthanasia for evaluation of selected haematology, coagulation and clinical chemistry parameters. All animals were subjected to a complete gross necropsy examination at scheduled euthanasia. Fresh organ weights were recorded, and selected tissues and organs were preserved from all animals. All tissues and organs collected at necropsy from five males and five females from each group and gross lesions from all animals were examined microscopically. No mortality occurred following repeated exposure to the test chemical. Clinical signs including urine stain, pre-dose salivation and post-dose salivation and post-dose wobbly gait were observed in the 225 and 750 mg/kg/day groups in both sexes. Remarkable clinical signs in the 75 mg/kg/day group were limited to a single incidence of post-dose salivation in one female. Mean forelimb grip strength and mean motor activity of males in the 750 mg/kg/day group were statistically lower than controls on day 29. No other toxicologically meaningful differences were noted in the functional observation battery. Statistically significant body weight loss occurred for males in the 750 mg/kg/day group during days 0-3. No other statistically significant differences in mean body weight change were noted for males or females in the 75, 225 or 750 mg/kg/day groups during the study. However, a tendency of reduced mean body weights (5-10 %) of males in the 750 mg/kg/day group were observed beginning on day 3 and continuing through day 30, although no significant differences were seen. Mean body weights of males in the 75 and 225 mg/kg/day groups and females in the 75, 225 and 750 mg/kg/day groups were comparable to controls throughout the study. Mean food consumption (grams/animal/day) of males and females in the 750 mg/kg/day group was statistically lower than controls during days 0-3 and remained lower but not statistically significant during days 16-30. No toxicologically relevant differences between the control, 75, 225 and 750 mg/kg/day groups were seen in the haematology parameters at study termination (days 33/34). A few statistically significant differences were noted however, none of the differences were considered toxicologically meaningful since they did not follow a consistent pattern and the mean values remained within the range of historical control data. Clinical biochemistry of the blood samples revealed higher mean total protein, calcium and cholesterol values for males in the 750 mg/kg/day group and higher mean cholesterol for females in the 750 mg/kg/day group, although the toxicological significance of these alterations were not clearly known. In addition, there was a common finding to both male and female animals that included a dose-related increase in total protein, albumin and globulin that appeared to correlate with a dose-related increase in liver weight. These changes were considered as treatment-related compensatory reaction to the test chemical possibly due to its metabolism. At necropsy, no remarkable gross necropsy findings were noted in the control, 75, 225 or 750 mg/kg groups and there were no toxicologically meaningful differences in absolute or relative organ weights between the groups. Moreover, no toxicologically significant test article-related microscopic lesions were noted in any of the tissues examined. A nondose-related, minimal to mild hyaline droplet nephropathy was observed for males in the 75, 225 and 750 mg/kg/day groups; however, this finding is not considered toxicologically significant for humans. In summary, repeated exposure to Acetophenone by oral route up to the concentration of 750 mg/kg bw/day induced reductions in body weight and food consumption as well as wobbly gait and urine stain in both males and females. In addition, the mean forelimb grip strength and mean motor activity of males of 750 mg/kg were statistically lower than the controls at the termination of the treatment. The NOAEL for the repeated dose toxicity endpoint was considered to be 225 mg/kg/day, based on clinical and neurobehavioral findings among high-dose animals.

Repeated dose toxicity: Inhalation

2'-acetonaphthone (CAS no 93-08-3) has very low vapor pressure of 0.0009 mm Hg at 21.9°C. So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely. Also, the particle size distribution was determined in the range of 500 micrometer to 1000 micron.Therefore this end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for2'-acetonaphthone (CAS no 93-08-3)(as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver

The NOAEL observed for the test chemical by repeated oral route of administration provided safety margins >1000 000 and >10 000 times the estimated daily per capita intakes in Europe and the USA respectively as cited in Evaluation of Certain Food Additives and Contaminants (WHO Technical Report Series 909, 2002). Considering this the test chemical does not pose a safety concern at currently estimated levels of use as a flavouring agent. Based on the data available for the test chemical, the test chemical does not exhibit toxicity upon repeated exposure by oral, inhalation and dermal route of exposure. Hence the test chemical is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

The NOAEL observed for the test chemical by repeated oral route of administration provided safety margins >1000 000 and >10 000 times the estimated daily per capita intakes in Europe and the USA respectively as cited in Evaluation of Certain Food Additives and Contaminants (WHO Technical Report Series 909, 2002). Considering this the test chemical does not pose a safety concern at currently estimated levels of use as a flavouring agent. Based on the data available for the test chemical, the test chemical does not exhibit toxicity upon repeated exposure by oral, inhalation and dermal route of exposure. Hence the test chemical is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.